1. Field
The present disclosure is directed to the use of an oligonucleotide for the preparation of a pharmaceutical composition suitable for intravenous administration for the prevention and/or treatment of tumors that are modulated by TGF-beta 1, TGF-beta 2, TGF-beta 3, VEGF, interleukin 10, c-jun, c-fos, MIA, and/or prostaglandin E2.
2. Discussion of the Background Art
Pancreatic carcinoma is one of the most aggressive human tumors. It is almost uniformly fatal and one of the leading causes of cancer-related death in the Western world. It is more common in males than in females. In most countries, the incidence ranges from 8 to 12 cases per 100 000, with a marked increase in Japan in the last few years. The lack of clinical symptoms usually leads to a diagnosis at a late stage of the disease. At the time of diagnosis, 85% of the patients have a locally advanced, non-resectable (stage II or stage III) or even metastatic (stage IV) carcinoma, with extra-pancreatic spread to distant organs such as liver or lung. Most patients succumb to the tumor's propensity to metastasize and its instrinsic resistance to cytotoxic agents and radiotherapy (Van Cutsem et al., 2007). Less than 3% of the patients are still alive 5 years after diagnosis despite receiving every available therapy. Pancreatic carcinoma is accompanied by severe clinical symptoms such as cachexia, pain, obstructive jaundice, and wasting, requiring intensive supportive care.
The available treatment options are scarce. Since pancreatic carcinomas are not very sensitive to chemotherapy, therapeutic agents such as 5-FU (5-fluorouracil), gemcitabine and oxaliplatin may alleviate symptoms, but the median survival is only 6 months. Gemcitabine has been widely accepted as the gold standard chemotherapy treatment, showing a median survival of about 6 months and a 1-year survival rate of about 20% (Burris et al., 1997). The tyrosine kinase inhibitor erlotinib, which targets epidermal-growth-factor-receptor (EGFR), was approved recently for first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer in combination with gemcitabine monotherapy (Moore et al., 2007).
Another type of cancer is the malignant melanoma, which is formed by melanocytes and occurs primarily in the skin, metastasizing rapidly throughout the body. Ultraviolet damage, immunosuppression, and congenital nevi are the predominant risk factors. The occurrence of this deadliest of all skin cancers has dramatically increased over the last few years, with the highest incidence found in Australia and New Zealand. Median survival for advanced stages (distant metastases) is 7 to 8 months, depending on the organ sites affected, and the 5-year survival rate is less than 5% (Young et al., 2006). An increased level of TGF-beta is expressed in all metastatic melanomas and in 94% of deeply invasive primary melanomas (Reed et al., 1994).
In principal, all melanoma lesions, including lymph nodes, are removed surgically. Radiotherapy provides symptomatic relief. When metastases are present, (adjuvant) chemotherapy such as nitrosureas or dacarbazine is the first choice, although rarely with curative potential and no improvement of survival. The response rate is with 10 to 20% rather modest and short-lived, with a response duration of about 3 months. The addition of high-dose interferon-alpha (IFN-alpha) or PEGylated IFN-alpha as immunotherapy enhances response rates, but does not influence the overall survival and involves substantial side effects. Similar findings appear to treatment with interleukin-2 (IL-2) with an even higher toxicity.
Colorectal carcinoma is a leading cause of morbidity and mortality. 5-year survival rates for stage III and IV are 67% and 10%, respectively (SEER 2004). The highest incidence rates of colorectal cancer are found in North America, Australia/New Zealand, Western Europe, and Japan with 30.1 to 49.3 per 100,000 for men and 20.1 to 36.0 for women.
Surgery is the primary treatment for colorectal carcinoma, and adjuvant chemo-, immuno-, or radiotherapy can be added, with the FOLFOX-regimen being the first line of care. The advent of agents such as capecitabine, irinotecan, and oxaliplatin as well as targeted agents such as cetuximab, erlotinib, and bevacizumab brought prolongation of survival to the treatment of colorectal carcinoma patients. Patients with metastatic disease, treated with such novel targeted therapies, can expect a median survival approaching 2 years (Kallinowski 2005), although with some severe side effects such as diarrhea, nausea, hemorrhages and bleeding, rash, allergic reactions, and heart problems with concomitant additional management cost. Despite this progress, 5-year survival rates are still very low for stage IV patients with 10% (SEER Program 2004), and the medical need for better treatment options is high. Multiple ongoing clinical trials are testing several combinations of chemotherapy and targeted therapies that mainly target EGFR and VEGF, with the aim to optimize current treatment. Other agents include those that inhibit the activity of the non-receptor tyrosine kinases, whereby both approaches are not specific enough on their own.
Hence, there is an urgent need for the improvement of tumor therapy, which may be reached with new compounds, combination of known compounds, or a variation of the dosage of compounds. An overall feature of pharmaceutical substances is their increasing efficacy accompanied by an increase in amounts being administered. Particular substances used in tumor therapy show a strong correlation between the total amount administered and the inhibition of tumor growth.
Additionally, cellular uptake is a limiting factor for the efficacy of “in vivo” administration of oligonucleotides, where conventionally high concentrations and high amounts of oligonucleotides are administered to inhibit the production of the respective protein.
Nevertheless, the clinical success of these substances is limited, since an increase in the concentration and the total amount of these substances, which can be administered to a mammal suffering from tumor metastases, nerval disease and immunosuppression, is correlated with a strong increase in severe side effects and toxicity.
EP 1 008 649 and EP 0 695 354 teach that oligonucleotides hybridizing with the mRNA of TGF-beta 1 and/or TGF-beta 2 can be used for manufacturing pharmaceutical compositions. EP 1 089 764 further teaches that inhibitors of substances negatively affecting the immune system in combination with oligonucleotides hybridizing with the mRNA of TGF-beta, VEGF, interleukin 10, and prostaglandin E2 and their respective receptors can be used for manufacturing a pharmaceutical composition as well. But these patents offer a wide range of concentrations in which the oligonucleotides can be administered. WO 2006/117400 A2 specifies dosages of oligonucleotides, which are used for the preparation of a pharmaceutical composition for preventing and/or treating cancer, and wherein the oligonucleotide is suitable for local administration in low concentrations.
Similar to its function in high-grade glioma, TGF-beta (-1, -2, and/or -3) appears to play a central role in malignancy and progression of pancreatic carcinoma (Friess et al., 1993; von Berstorff, et al., 2001), malignant melanoma (Reed et al., 1994), and colorectal carcinoma, respectively. Given the limited progress achieved in the treatment of pancreatic carcinoma, malignant melanoma, and colorectal carcinoma in recent years, the need for more effective therapies in terms of prolonged survival is obvious.
A solution to this problem is provided by the present disclosure described in the following, which is directed to a method of preventing and/or treating a tumor with an oligonucleotide comprising 8 to 30 nucleotide building blocks, which hybridizes with mRNA of TGF-beta 1, -2, -3, VEGF, interleukin-10, c-jun, c-fos, MIA, and/or prostaglandin E2 wherein the antisense oligonucleotide is administered intravenously or subcutaneously.